Interleukin-17 (“IL-17”), also known as IL-17A and CTLA-8, is a pro-inflammatory cytokine that stimulates secretion of various other cytokines in a variety of cell types. For example, IL-17 can induce IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ, as well as numerous chemokines and other effectors. See, e.g., Gaffen, S L, Arthritis Research & Therapy 6: 240-247 (2004).
IL-17 is expressed by TH17 cells, which are involved in the pathology of inflammation and autoimmunity. It is also expressed by CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages and dendritic cells. IL-17 and Th17 are linked to pathogenesis of diverse autoimmune and inflammatory diseases, but are essential to host defense against many microbes, particularly extracellular bacteria and fungi. Human IL-17A is a glycoprotein with a molecular weight of 17,000 daltons (Spriggs et al., J Clin Immunol, 17: 366-369 (1997)). IL-17 can form homodimers or heterodimers with its family member, IL-17F. IL-17 binds to both IL-17 RA and IL-17 RC to mediate signaling. IL-17, signaling through its receptor, activates the NF-κB transcription factor, as well as various MAPKs. See, e.g., Gaffen, S L, Nature Rev Immunol, 9: 556-567 (2009).
IL-17 can act in cooperation with other inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β to mediate pro-inflammatory effects. See, e.g., Gaffen, S L, Arthritis Research & Therapy 6: 240-247 (2004). Increased levels of IL-17 have been implicated in numerous diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, angiogenesis, atherosclerosis, asthma, and multiple sclerosis. See, e.g., Gaffen, S L, Arthritis Research & Therapy 6: 240-247 (2004); US Publication No 20080269467 A1, published Oct. 30, 2008. IL-17 was found in higher serum concentrations in patients with systemic lupus erythematosus (SLE) and was recently determined to act either alone or in synergy with B-cell activating factor (BAFF) to control B-cell survival, proliferation, and differentiation into immunoglobulin producing cells. Doreau et al., Nature Immunology 7:778-785 (2009). IL-17 has also been associated with ocular surface disorders, such as dry eye (PCT publication WO2010062858 and WO2011163452). IL-17 has also been implicated in playing a role in ankylosing spondylitis (H. Appel et al., Arthritis Research and Therapy 2011, 13R95) and psoriatic arthritis (McInnes, I. et al. Arthritis & Rheumatism, 2011; Volume 63, Suppl. 10:779).
IL-17 and IL-17-producing TH17 cells have recently been implicated in certain cancers, Ji and Zhang, Cancer Immunol Immunother 59: 979-987 (2010). For example, IL-17-expressing TH17 cells were shown to be involved in multiple myeloma, Prabhala et al., Blood, online DOI 10.1182/blood-2009-10-246660, Apr. 15, 2010, and to correlate with poor prognosis in patients with hepatocellular carcinoma (HCC), Zhang et al., J Hepatology 50: 980-89 (2009). Also, IL-17 was found to be expressed by breast-cancer-associated macrophages, Zhu et al., Breast Cancer Research 10:R95 (2008). However, the role of IL-17 in cancer, in many cases, has been unclear. In particular, IL-17 and IL-17-producing TH17 cells have been identified as having both a positive and a negative role in tumor immunity, sometimes in the same type of cancer. For a review, see, Ji and Zhang, Cancer Immunol Immuother 59: 979-987 (2010).
It can be seen from above that modulation of IL-17 has important therapeutic implications. Although various antibodies to IL-17 have been described in the prior art, very few small molecule-type, specific modulators of IL-17 with oral bioavailability are known. Accordingly, there is a need for the development of small molecule-like modulators of IL-17.